Nox4 and the Redox-Regulation of MKPs in Monocyte Recruitment and Atherosclerosis

描述（由申请人提供）：趋化因子驱动的单核细胞迁移到内皮下空间是动脉粥样硬化发生的基本和限速过程。我们的初步数据表明，这一过程被代谢应激失调，单核细胞对趋化因子的反应性增加似乎加速了动脉粥样硬化斑块的发展。我们现在已经发现了单核细胞中一种新的硫醇氧化还原敏感机制，该机制在代谢紊乱的失调下，“启动”并将单核细胞转化为超趋化的促动脉粥样硬化表型。此外，我们发现最近发现的单核细胞NADPH氧化酶4是单核细胞启动的介质。我们认为代谢应激诱导的Nox4和随后单核细胞中H2O2形成的增加促进了s-谷胱甘肽化和丝裂原活化的蛋白激酶磷酸酶（MPKs）的失活；MKPs是负责磷酸化erk和磷酸化p38mapk失活的酶，这是介导mcp -1诱导的单核细胞粘附和迁移的两种主要MAPK途径。我们假设单核细胞mpk代表了代谢紊乱引起的氧化应激与动脉粥样硬化病变形成之间的一种新的、关键的机制联系。我们的研究支持一个新的范式，即单核细胞启动和功能障碍是动脉粥样硬化发生的早期主要因素。我们在此提出的研究旨在验证这一范式并阐明潜在的分子机制。特异性目的1：确定丝裂原激活的蛋白激酶磷酸酶（MKP）在单核细胞粘附、趋化和动脉粥样硬化病变募集的氧化还原调节中的作用。特异性目的2：确定蛋白- s -谷胱甘肽化在单核细胞募集和动脉粥样硬化病变发展中的作用。特异性目的3：确定单核细胞Nox4在单核细胞启动和动脉粥样硬化中的作用。

DESCRIPTION (provided by applicant): Chemokine-driven transmigration of monocytes into the subendothelial space is a fundamental and rate- limiting process in atherogenesis. Our preliminary data show that this process is dysregulated by metabolic stress and that increased monocyte responsiveness to chemokines appears to accelerate atherosclerotic plaque development. We have now uncovered a novel thiol redox-sensitive mechanism in monocytes that upon dysregulation by metabolic disorders, "primes" and transforms monocytes into a hyper-chemotactic pro- atherogenic phenotype. In addition, we have found that the recently discovered monocytic NADPH oxidase 4 is a mediator of monocyte priming. We propose that metabolic stress-induced Nox4 and the subsequent increase in H2O2 formation in monocytes promote the S-glutathionylation and inactivation of mitogen-activated protein kinase phosphatases (MPKs); MKPs are the enzymes responsible for the deactivation of both phospho-ERK and phospho-p38MAPK, the two principal MAPK pathways mediating MCP-1-induced monocyte adhesions and migration. We hypothesize that monocyte MPKs represent a novel, critical mechanistic link between oxidative stress induced by metabolic disorders and the formation of atherosclerotic lesions. Our studies support a new paradigm implicating monocyte priming and dysfunction as an early primary contributor to atherogenesis. The studies we propose here aim to test this paradigm and elucidate the underlying molecular mechanisms. Specific Aim 1: Determine the roles of mitogen-activated protein kinase phosphatases (MKP) in the redox regulation of monocyte adhesion, chemotaxis, and recruitment into atherosclerotic lesions. Specific Aim 2: Determine the roles of protein-S-glutathionylation in monocyte recruitment and the development of atherosclerotic lesions. Specific Aim 3: Determine the roles of monocytic Nox4 in monocyte priming and atherogenesis.